Letter Cite This: ACS Macro Lett. 2018, 7, 159−165
pubs.acs.org/macroletters
Overcoming Surfactant-Induced Morphology Instability of Noncrosslinked Diblock Copolymer Nano-Objects Obtained by RAFT Emulsion Polymerization Nghia P. Truong,† Cheng Zhang,‡,§ Tuan A.H. Nguyen,∥ Athina Anastasaki,⊥ Morgan W. Schulze,⊥ John F. Quinn,† Andrew K. Whittaker,‡,§ Craig J. Hawker,⊥ Michael R. Whittaker,*,† and Thomas P. Davis*,†,# †
ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia ‡ Australian Institute for Bioengineering and Nanotechnology, §ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and ∥School of Chemical Engineering, The University of Queensland, Brisbane, Queensland 4072, Australia ⊥ Materials Research Laboratory, University of California, Santa Barbara, California 93106, United States # Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom S Supporting Information *
ABSTRACT: RAFT emulsion polymerization techniques including polymerization-induced self-assembly (PISA) and temperature-induced morphological transformation (TIMT) are widely used to produce noncrosslinked nano-objects with various morphologies. However, the worm, vesicle and lamellar morphologies produced by these techniques typically cannot tolerate the presence of added surfactants, thus limiting their potential applications. Herein we report the surfactant tolerance of noncrosslinked worms, vesicles, and lamellae prepared by RAFT emulsion polymerizations using poly(di(ethylene glycol) ethyl ether methacrylate-co-N-(2-hydroxypropyl) methacrylamide) (P(DEGMA-coHPMA)) as a macromolecular chain transfer agent (macro-CTA). Significantly, these P(DEGMA-co-HPMA) nanoparticles are highly stable in concentrated solutions of surfactants (e.g., sodium dodecyl sulfate (SDS)). We also demonstrate that the surfactant tolerance is related to the limited binding of SDS to the mainchain of the P(DEGMA-co-HPMA) macro-CTA constituting the particle shell. This work provides new insight into the interactions between surfactants and thermoresponsive copolymers and expands the scope of RAFT emulsion polymerization techniques for the preparation of noncrosslinked and surfactant-tolerant nanomaterials.
The morphology of polymeric nanomaterials has been identified as a crucial factor that impacts their properties and applications.1,2 Elongated shape is beneficial to building blocks for three-dimensional superstructures, templates for catalysis, and extracellular matrices for tissue engineering.3,4 In nanomedicine, morphology affects various biological parameters including circulation time, biodistribution, cellular uptake, and efficiency of nanocarriers.5−7 The synthesis of nanomaterials with stable morphologies is therefore critical and has attracted increasing attention.8 Reversible addition−fragmentation chain transfer (RAFT) emulsion polymerization techniques including polymerizationinduced self-assembly (PISA) and temperature-induced morphological transformation (TIMT) have been recognized as simple, rapid, and environmentally friendly methods for the scalable synthesis of polymeric nano-objects with different morphologies.9,10 In PISA, water-soluble macromolecular chain transfer agents (macro-CTAs) are copolymerized with waterinsoluble monomers to form in situ core−shell micelles of tunable size and shape.11−14 In TIMT, thermoresponsive rather © XXXX American Chemical Society
than water-soluble macro-CTAs are employed (e.g., thermoresponsive poly((di(ethylene glycol) methyl ether methacrylate)-co-N-(2-hydroxypropyl) methacrylamide) (P(DEGMA-coHPMA)).15,16 Nanomaterials produced by these techniques have been used for diverse applications.17,18 Notwithstanding the advantages outlined above, the current limitation of the RAFT emulsion polymerization is that the morphologies of noncrosslinked diblock copolymer nanoparticles typically are not stable in a concentrated solution of surfactant.19 The addition of anionic surfactant to suspensions of nano-objects prepared by PISA leads to the rapid dissociation of these nanomaterials to molecularly dissolved copolymer chains.20 In addition, worm, vesicle and lamellar morphologies prepared by TIMT were all transformed to a spherical shape when sodium dodecyl sulfate (SDS) was Received: December 17, 2017 Accepted: January 8, 2018
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DOI: 10.1021/acsmacrolett.7b00978 ACS Macro Lett. 2018, 7, 159−165
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ACS Macro Letters added.21 The destruction and morphological instability of these nano-objects are attributed to the increased solubility of polymer chains or the decrease in the critical packing parameter (p) of the nano-objects due to the binding of SDS to the macro-CTAs constituting the nanoparticle shell.20−22 This drawback critically limits the potential applications of these synthetic techniques, particularly for home and personal care products.19 Considerable efforts have been made to overcome the surfactant-induced instability of these nanoparticle morphologies by covalently cross-linking the nano-objects.23,24 For example, Armes and co-workers have developed a postmodification technique using epoxy-amine chemistry to crosslink the hydrophilic domain of the vesicle membrane.20 An and colleagues used an asymmetric cross-linker bearing two vinyl groups of different reactivities to in situ cross-link the hydrophobic part of the vesicle membrane.25−27 The use of cross-linkers is likely to increase colloidal instability, is less reliable for worm morphology and, more importantly, is not applicable for stimuli-responsive nanomaterials. 19 These inherent disadvantages require urgent alternative solutions.28 A potential approach to overcome this surfactant induced morphology instability without the use of cross-linkers is to employ macro-CTAs that have limited binding with surfactants. In nanomedicine, poly(ethylene glycol) (PEG) and PHPMA are widely used as antifouling polymers to reduce the binding of surfactant-like molecules (e.g., proteins).29,30 However, to date there has been no comprehensive study on the binding of surfactants to ethylene glycol- and PHPMA-based thermoresponsive copolymers such as P(DEGMA-co-HPMA). In addition, it remains unclear whether noncrosslinked nanoparticles having P(DEGMA-co-HPMA) as the corona are stable in the presence of added surfactants. To address this challenge, we studied the surfactant tolerance of nano-objects prepared by RAFT emulsion polymerization using P(DEGMA-co-HPMA) as the macro-CTA and investigated interactions between this thermoresponsive polymer and SDS. First, nanoparticles having worm, vesicle and lamellar morphologies were synthesized by RAFT emulsion polymerization. The morphologies and the surfactant tolerance of these nanoparticles were characterized by transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS). Next, the interaction between P(DEGMA-co-HPMA) macroCTA and SDS was investigated using molecular dynamics (MD) simulation and nuclear Overhauser effect spectroscopy (NOESY). Finally, pulsed-field gradient NMR (PFG-NMR) was employed to estimate the mole fraction of SDS bound to the macro-CTA. To prepare nano-objects with various morphologies (Scheme 1), RAFT emulsion polymerizations using the P(DEGMA29-coHPMA 6 ) macro-CTA were carried out as previously described.31 The hot suspension obtained after polymerization was cooled to ambient temperature (T < cloud point temperature (Tcp)) in the presence of appropriate amounts of added plasticizer (toluene for polystyrene (PS), propyl methacrylate (PMA) for PPMA).32 During cooling, the thermoresponsive block of the diblock copolymer (∼19 mg mL−1) transitioned from water-insoluble to water-soluble, which induced the reorganization of the diblock copolymer chains and the transformation of the initially self-assembled spheres to other morphologies (worm, vesicle, or lamellae).15
Scheme 1. (A) Synthesis of Worms, Vesicles, and Lamellae via RAFT Emulsion Polymerization of Styrene and (B) Representative Cartoons for Temperature-Induced Morphological Transformation
The cloudy suspensions were obtained (denoted as latexes) and characterized by TEM. Figure 1A−C showed worm, a mixture of worm and vesicle, and lamellar morphologies when different concentrations of plasticizer were added (40, 80, and 160 μL mL−1, respectively). This result is consistent with our previous observations, thus, highlighting the reproducibility of
Figure 1. Upper row shows representative TEM images of the polystyrene latexes after emulsion polymerization and addition of (A) 40, (B) 80, and (C) 160 μL mL−1 of toluene, followed by cooling to room temperature for 24 h. Bottom row shows representative TEM images of latexes (D), (E), and (F) obtained by adding SDS (5 mg) to latexes (A), (B), and (C) (0.5 mL), respectively. Scale bars for (B) and (E) were 1 μm. Other scale bars represent 0.5 μm. 160
DOI: 10.1021/acsmacrolett.7b00978 ACS Macro Lett. 2018, 7, 159−165
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ACS Macro Letters the TIMT technique.31 To identify if there is a small decrease in the p value upon adding SDS, we synthesized a mixture of worms and vesicles (p ∼ 1/2) but not pure vesicles (1 > p > 1/ 2) because a small decrease in the p value of pure vesicles (e.g., from p ∼ 0.7 to p ∼ 0.6) is not expected to result in the loss of this morphology. In addition to using plasticizer, the morphology of the nanoparticles prepared by TIMT has been also controlled via manipulating the molecular weight of the thermoresponsive and the water-insoluble block.31 However, changing the molecular weight of diblock copolymers has been found to affect the stability of their nanoparticles (e.g., aggregation or dissolution).33,34 As such, we have chosen to tune the nanoparticle shape by using plasticizers in order to decouple polymer molecular weight from particle stability. Next, SDS (5 mg) was added to the latexes of worms, mixed worms and vesicles, and lamellae (0.5 mL), vortexed for 1 min, and subsequently characterized by TEM. Interestingly, Figure 1D−F showed that morphologies of all nano-objects made from the P(DEGMA29-co-HPMA6) macro-CTA were stable in concentrated SDS solution (up to 10 mg mL−1). To complement these TEM images, SAXS was used to analyze the worm morphology in solution with and without adding SDS by fitting the scattering profiles to a theoretical model for cylindrical objects.35 In Figure 2A, the scattering profile of the
The surfactant tolerance identified in this work is in stark contrast to the surfactant-induced dissociation or morphological transformation found for the majority of noncrosslinked nano-objects previously prepared by PISA and TIMT.19 For example, worms, vesicles, and lamellae comprising a similar PS core but a thermoresponsive poly(N-isopropylacrylmide)(PNIPAM) shell have been found to transform into spheres when SDS was added.21 This transformation is related to a decrease in the critical packing parameter (p).21Particularly, on adding SDS to the latexes of PS-b-PNIPAM nanoparticles, the added SDS molecules bind to the PNIPAM side chains of the particle surface.21 This binding increases the effective interfacial area at the hydrophobic−water interface (a) such that the packing parameter decreases to a value consistent with a spherical morphology (p < 1/3), as given by Particularly, on adding SDS to the latexes of PS-b-PNIPAM nanoparticles, the added SDS molecules bind to the PNIPAM side chains of the particle surface.21 This binding increases the effective interfacial area at the hydrophobic−water interface (a) such that the packing parameter decreases to a value consistent with a spherical morphology (p < 1/3), as given by eq 1:37 p = ν /al
(1)
where p is the critical packing parameter; ν is the volume of hydrophobic chains; a is an effective interfacial area at the hydrophobic−water interface; and l is the length of hydrophobic chains. In contrast, the packing parameter of P(DEGMA29-coHPMA6) nanoparticles exhibited no significant change upon the addition of SDS as demonstrated by the high stability of worms, lamellae and the mixture of worms and vesicles. As detailed above, even a small decrease in the p value upon adding SDS to the latex of worms and vesicles (from p ∼ 1/2 for worms and vesicles to p < 1/2 for worms only) typically results in the disappearance of the vesicle morphology. However, the vesicle morphology was clearly observed in Figure 1E, suggesting that the p value was unchanged. Further, the plasticizer (toluene) remained inside the swollen PS cores so the morphologies of these nano-objects were not kinetically frozen due to the glassy PS core (Tg,PS = 95 °C).16 Similarly, nano-objects with a P(DEGMA29-co-HPMA6) shell and less glassy PPMA core (Tg,PPMA = 31 °C)16 were also tolerant to added SDS (Figure S2). Based on these observations, we hypothesize that added SDS has limited binding to P(DEGMA29-co-HPMA6) domains so that the packing parameter remains unchanged upon adding SDS. While the interactions between SDS and thermoresponsive PNIPAM have been welldocumented in the literature,38 the binding of surfactants to ethylene glycol- and PHPMA-based thermoresponsive copolymers has not been investigated. To study the molecular interaction between SDS and P(DEGMA 29 -co-HPMA 6 ) at ambient temperature, 2D NOESY NMR was initially employed. The mixing time and other parameters used for NOESY NMR were carefully chosen.39−41 In Figure 3A, strong positive cross-relaxation peaks between representative alkyl protons for the SDS surfactant (peak g) and those of the P(DEGMA29-coHPMA6) domains are clearly observed. This observation suggested that at ambient temperature, SDS molecules associated closely to P(DEGMA29-co-HPMA6) chains, typically over distances smaller than 0.5 nm.42 This association is similar to the binding of SDS to PNIPAM at ambient temperature reported by Chen et al.38 While the association is similar, the
Figure 2. SAXS patterns for the worm latex (A) before and (B) after the addition of SDS (10 mg mL−1) at ambient temperature. The black solid line is theoretical fitting of experimental data to a cylindrical model using SASview software.
worm latex was satisfactorily fit using a cylindrical model (black solid line) suggesting that the majority of nanoparticles in solution had worm-like morphology.36 Importantly, the scattering profile of the worm latex upon the addition of SDS (Figure 2B) revealed a similar pattern in agreement with the cylindrical model, thus, confirming that the P(DEGMA29-coHPMA6) nanoparticles were stable in the presence of added SDS. Significantly, the worm latex was also highly stable in the presence of alternative surfactants such as cationic decyltrimethylammonium bromide (Figure S1). These results illustrate the robust and stable nature of polymeric nanostructures based on P(DEGMA29-co-HPMA6) in concentrated surfactant solutions. 161
DOI: 10.1021/acsmacrolett.7b00978 ACS Macro Lett. 2018, 7, 159−165
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ACS Macro Letters
Figure 4. (A) Normalized cross-peak intensities at different temperatures. (B) Pair distribution function vs distance between protons g of SDS and protons h of P(DEGMA29-co-HPMA6) at 298 and 338 K.
Figure 3. (A) 1H−1H 2D NOESY spectrum of P(DEGMA29-coHPMA6)/SDS/D2O solution (12.5 mg/0.25 mg/1 mL). (B) Normalized cross-peak intensities at ambient temperature of protons g to protons of P(DEGMA29-co-HPMA6). These values were calculated from the NOESY spectrum by using the diagonal crosspeaks generated from the methylene protons from SDS.
stabilization of P(DEGMA29-co-HPMA6) particles formed at 70 °C during emulsion polymerization indicates that a fraction of the SDS molecules remains associated with the P(DEGMA29-co-HPMA6) domains of the nanoparticles. To quantitatively estimate the mole fraction of SDS bound to P(DEGMA29-co-HPMA6) chains, self-diffusion coefficients (D) were determined using PFG-NMR (see the experimental for more details).43,44 The quality of the fit of a single diffusion coefficient to the echo attenuation data was extremely good (Figure S3). Moreover, the presence of a second component in the plots can be confidently excluded. Previously, Chen and coworkers have employed a similar strategy to determine the molar percentage of SDS molecules bound to PNIPAM chains under comparable conditions.38 In this analysis, the mole fractions of SDS molecules bound to P(DEGMA29-co-HPMA6) chains ( f bound) at various temperatures and concentrations were calculated as using eq 2:45
binding sites of SDS to the P(DEGMA29-co-HPMA6) chains is distinctly different to that observed for PNIPAM. As shown in Figure 3B, the normalized cross-peak intensity between the alkyl protons of SDS (peak g) and the protons of P(DEGMA29co-HPMA6) backbone (peak h) is significantly higher than for the P(DEGMA 29 -co-HPMA 6 ) side chains (peaks a−f), indicating that SDS associates primarily with the backbone of P(DEGMA29-co-HPMA6) chains. In contrast, SDS associates strongly with the isopropyl group of the PNIPAM side chain.38 These NOESY NMR studies provide a useful molecular-level understanding of the interactions between SDS and P(DEGMA29-co-HPMA6) at ambient temperature. To further understand the interaction between SDS and P(DEGMA29-co-HPMA6), 1H NOESY experiments were conducted at a series of elevated temperatures with the results being supported by MD simulations. At temperatures above the Tcp, the association of SDS molecules with the P(DEGMA29-coHPMA6) backbone decreases, which is similar to the behavior observed between SDS and PNIPAM at higher temperatures.38 In particular, Figure 4A showed a decrease in normalized crosspeak intensities between the protons g and those of P(DEGMA29-co-HPMA6), indicating the dissociation of SDS/ P(DEGMA29-co-HPMA6) as the solution temperature increased. The dissociation observed by NOESY NMR is in close agreement with the data obtained by MD simulation, indicating that the distance between protons g of SDS and protons h of the P(DEGMA29-co-HPMA6) backbone increased at higher temperature (Figure 4B). Taken together, both NOESY NMR and MD simulation results suggest that the binding between SDS and P(DEGMA29-co-HPMA6) is dynamic and sensitive to increasing temperature. However, the
Dobs = ffree Dfree + fbound D bound
(2)
where Dobs is the single, observed self-diffusion coefficient of SDS, f free is the mole fraction of free SDS, Dfree is the selfdiffusion coefficient of SDS measured in a solution in the absence of the polymer, f bound is the mole fraction of SDS bound to the polymer chains, and Dbound is the self-diffusion coefficient of the bound SDS, assumed to be the same as the measured diffusion coefficient for the polymer.45 In Table 1, f bound is shown to decrease when the solution temperature is higher than the Tcp. Significantly, a large number of SDS molecules are still associated with the P(DEGMA29-coHPMA6) chains, even at temperatures well above the Tcp. This result is consistent with the partial dissociation of SDS/ P(DEGMA29-co-HPMA6) at elevated temperature observed in the NOESY NMR results while the observation of bound SDS explains the stabilization of P(DEGMA29-co-HPMA6) particles 162
DOI: 10.1021/acsmacrolett.7b00978 ACS Macro Lett. 2018, 7, 159−165
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ACS Macro Letters ORCID
Table 1. Diffusion Coefficients (D) and Mole Fractions of SDS-Bound Polymer (f bound)
Nghia P. Truong: 0000-0001-9900-2644 John F. Quinn: 0000-0002-4593-1170 Andrew K. Whittaker: 0000-0002-1948-8355 Craig J. Hawker: 0000-0001-9951-851X Michael R. Whittaker: 0000-0001-5706-3932 Thomas P. Davis: 0000-0003-2581-4986
D × 1010 (m2·s−1) −1
T (K)
[SDS] (mg mL )
Dfree
Dobs
Dbound
f bound
298 308 318 328 298 298 298
0.25 0.25 0.25 0.25 1.25 2.50 10.0
7.53 10.4 12.5 15.7 7.41 6.53 1.95
1.67 0.95 3.93 6.45 1.54 1.64 1.53
1.48 0.81 2.45 3.34 1.43 1.40 1.12
1.0 1.0 0.9 0.8 1.0 1.0 0.5
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Electron microscopy was performed at the Bio21 Advanced Microscopy Facility, The University of Melbourne. SAXS experiments were performed at Beamline 1-5 of Stanford Synchrotron Radiation Lightsource (SSRL). Use of the SSRL, a Directorate of the SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC0276SF0051. This work benefited from the use of the SasView application, originally developed under NSF Award DMR0520547. SasView contains code developed with funding from the European Union’s Horizon 2020 research and innovation programme under the SINE2020 Project, Grant Agreement No. 654000. This work was carried out within the Australian Research Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology (Project No. CE140100036). N.P.T. acknowledges the award of a DECRA Fellowship from the Australian Research Council (DE180100076). C.Z. acknowledges the University of Queensland for his Early Career Researcher Grant (UQECR1720289). T.A.H.N. acknowledges the University of Queensland for his Early Career Researcher Grant (UQECR1720169). A.A. is grateful to the European Union (EU) for a Marie Curie Postdoctoral Fellowship and the California NanoSystems Institute for an Elings Prize Fellowship in Experimental Science. J.F.Q. acknowledges receipt of a Future Fellowship from the ARC (FT170100144). T.P.D. is grateful for the award of an Australian Laureate Fellowship from the ARC (FL140100052).
formed at high temperature prior to and during the emulsion polymerization. Furthermore, at ambient temperature, f bound also decreased at the SDS concentration of 10 mg mL−1 (well above the critical micellization concentration of SDS, 2.5 mg mL−1),38 indicating that a large portion of added SDS molecules tended to form SDS aggregates (with alkyl groups as the core and sulfate groups as the shell) rather than coassembly with P(DEGMA29-co-HPMA6) chains.46 Altogether, the data obtained from the PFG-NMR supported our hypothesis that a limited amount of added SDS binds to P(DEGMA29-co-HPMA6) chains, thus leading to the surfactant tolerance of noncrosslinked nanoparticles made from P(DEGMA-co-HPMA) macro-CTA. Further, the nature of the binding between SDS and P(DEGMA-co-HPMA) is dynamic and sensitive to both temperature and SDS concentration. In conclusion, we have demonstrated the enhanced stability in concentrated surfactant solutions and the morphological richness of noncrosslinked nano-objects prepared by RAFT emulsion polymerization using P(DEGMA29-co-HPMA6) as a macro-CTA. The combination of NOESY, PFG-NMR, and MD simulations reveals that at low temperature and concentration, SDS molecules bind to the backbone of P(DEGMA29-co-HPMA6) with partial dissociation of this assembly occurring as elevated temperatures. A significant fraction of SDS remains bound at elevated temperatures providing colloidal stability to P(DEGMA29-co-HPMA6) particles formed at the beginning and during the emulsion polymerization process. These findings illustrate a distinct interaction between SDS and the thermoresponsive P(DEGMA29-co-HPMA6) chains as well as the mechanism of SDS-stabilized thermoresponsive nanoparticles. Significantly, the morphologies of the noncrosslinked P(DEGMA-co-HPMA) particles are not affected by the introduction of SDS at room temperature leading to the surfactant tolerance and increasing the applicability of noncrosslinked nano-objects prepared by RAFT emulsion polymerization techniques.
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(1) Hinde, E.; Thammasiraphop, K.; Duong, H. T.; Yeow, J.; Karagoz, B.; Boyer, C.; Gooding, J. J.; Gaus, K. Pair correlation microscopy reveals the role of nanoparticle shape in intracellular transport and site of drug release. Nat. Nanotechnol. 2016, 12 (1), 81− 89. (2) Ta, H. T.; Truong, N. P.; Whittaker, A. K.; Davis, T. P.; Peter, K. The effects of particle size, shape, density and flow characteristics on particle margination to vascular walls in cardiovascular diseases. Expert Opin. Drug Delivery 2018, 15, 33−45. (3) Truong, N. P.; Quinn, J. F.; Whittaker, M. R.; Davis, T. P. Polymeric filomicelles and nanoworms: two decades of synthesis and application. Polym. Chem. 2016, 7 (26), 4295−4312. (4) Cheng, C.; Qi, K.; Germack, D. S.; Khoshdel, E.; Wooley, K. L. Synthesis of core-crosslinked nanoparticles with controlled cylindrical shape and narrowly-dispersed size via core-shell brush block copolymer templates. Adv. Mater. 2007, 19 (19), 2830. (5) Truong, N. P.; Whittaker, M. R.; Mak, C. W.; Davis, T. P. The importance of nanoparticle shape in cancer drug delivery. Expert Opin. Drug Delivery 2015, 12 (1), 129−142. (6) Kaga, S.; Truong, N. P.; Esser, L.; Senyschyn, D.; Sanyal, A.; Sanyal, R.; Quinn, J. F.; Davis, T. P.; Kaminskas, L. M.; Whittaker, M. R. Influence of Size and Shape on the Biodistribution of Nanoparticles
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.7b00978. Experimental details (PDF).
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REFERENCES
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. 163
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